Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure:

Citalopram may be prepared by ring closure of 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile (racemic citalopram diol) as described in U.S. Pat. No. 4,650,884. The product citalopram is a racemic mixture of the R- and S-enantiomers.
Further, the S-enantiomer of citalopram (escitalopram) is a valuable antidepressant of the selective serotonin reuptake inhibitor (SSRI) type. Escitalopram may be prepared by ring closure of S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile (S-diol) with retention of configuration as described in EP B1 347 066. The amount of R-citalopram compared to S-citalopram in the product escitalopram should be less than 3%.
Furthermore, a method for the preparation of a mixture of R- and S-citalopram with more than 50% of the S-enatiomer from a mixture of R- and S-diol with more than 50% of the R-diol is described in WO03000672.
It appears from the above, that products of racemic citalopram and escitalopram with the above-mentioned enantiomeric purity are required for the preparation of pharmaceutical compositions and that racemic citalopram and escitalopram products may be prepared by ring closure of the RS-diol and R-diol and/or S-diol. As a consequence, methods for the preparation of products of racemic diol and S-diol being correspondingly enantiomerically pure are required.
Processes for the preparation and purification of R- or S-diol products are available. Such processes involve for instance enantio-selective synthesis as described in EP 0347066, classical resolution and chromatographic separation as described in WO03006449. Depending on the specific process and the conditions used, the enantiomeric purity of the S-diol product may have to be improved before the S-diol product will meet the above requirements.
Surprisingly, it has now been found that by using the process of the invention an expensive, but apparently useless S-diol product being contaminated with R-diol, may easily be converted into the two valuable products, racemic diol and S-diol, which meet the above requirements as regards enantiomeric purity.
Furthermore, by using the process of the invention, an expensive, but apparently useless R-diol product being contaminated with S-diol, may easily be converted into the valuable products, racemic diol and R-diol, which meet the above requirements as regards enantiomeric purity.
More particularly, the present invention provides a process for the separation of an initial non-racemic mixture of R- and S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile with more than 50% of one of the enantiomers into a fraction being enriched with S-diol or R-diol and a fraction comprising RS-diol, wherein the ratio of R-diol:S-diol is equal to 1:1 or closer to 1:1 than in the initial mixture of R- and S-diol.
The process of the invention is important and very useful, in particular because it provides a convenient, cheap and efficient way to transform a mixture of R- and S-diols which does not meet the above requirements as regards enantiomeric purity into two valuable products, RS-diol and S-diol (or R-diol), which meet the above requirements as regards enantiomeric purity.
In another aspect, the invention provides a convenient, cheap and efficient method for making an intermediate to be used in the manufacturing of citalopram and escitalopram.
With the present invention, the process for the production of racemic citalopram and escitalopram meeting the requirements of the respective marketing approvals has become more rational and more economical as regards the simplicity of the process and the utilisation of reagents and resources.